Diversification of circulating and tumor-infiltrating plasmacytoid DCs towards the P3 (CD80+ PDL1-)-pDC subset negatively correlated with clinical outcomes in melanoma patients

Eleonora Sosa Cuevas; Nathalie Bendriss-Vermare; Stephane Mouret; Florence De Fraipont; Julie Charles; Jenny Valladeau-Guilemond; Laurence Chaperot; Caroline Aspord

doi:10.1002/cti2.1382

Diversification of circulating and tumor-infiltrating plasmacytoid DCs towards the P3 (CD80⁺ PDL1^-)-pDC subset negatively correlated with clinical outcomes in melanoma patients

Clin Transl Immunology. 2022 May 3;11(5):e1382. doi: 10.1002/cti2.1382. eCollection 2022.

Authors

Affiliations

¹ Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes Grenoble France.
² Etablissement Français du Sang Auvergne-Rhône-Alpes R&D Laboratory Grenoble France.
³ Univ Lyon Université Claude Bernard Lyon 1 INSERM 1052 CNRS 5286 Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon Lyon France.
⁴ Dermatology Clinic Grenoble University Hospital Grenoble France.
⁵ Medical Unit of Molecular Genetic (Hereditary Diseases and Oncology) Grenoble University Hospital Grenoble France.

Abstract

Objectives: Plasmacytoid DCs (pDCs) play a critical yet enigmatic role in antitumor immunity through their pleiotropic immunomodulatory functions. Despite proof of pDC diversity in several physiological or pathological contexts, pDCs have been studied as a whole population so far in cancer. The assessment of individual pDC subsets is needed to fully grasp their involvement in cancer immunity, especially in melanoma where pDC subsets are largely unknown and remain to be uncovered.

Methods: We explored for the first time the features of diverse circulating and tumor-infiltrating pDC subsets in melanoma patients using multi-parametric flow cytometry, and assessed their clinical relevance. Based on CD80, PDL1, CD2, LAG3 and Axl markers, we provided an integrated overview of the frequency, basal activation status and functional features of pDC subsets in melanoma patients together with their relationship to clinical outcome.

Results: Strikingly, we demonstrated that P3-pDCs (CD80⁺PDL1^-) accumulated within the tumor of melanoma patients and negatively correlated with clinical outcomes. The basal activation status, diversification towards P1-/P2-/P3-pDCs and functionality of several pDC subsets upon TLR7/TLR9 triggering were perturbed in melanoma patients, and were differentially linked to clinical outcome.

Conclusion: Our study shed light for the first time on the phenotypic and functional heterogeneity of pDCs in the blood and tumor of melanoma patients and their potential involvement in shaping clinical outcomes. Such novelty brightens our understanding of pDC complexity, and prompts the further deciphering of pDCs' features to better apprehend and exploit these potent immune players. It highlights the importance of considering pDC diversity when developing pDC-based therapeutic strategies to ensure optimal clinical success.

Keywords: clinical outcome; immune subversion; melanoma; pDC subsets.